miR-23a靶向调控ADAM10基因在颞叶癫痫中的作用及其机制研究

Micro RNA (miRNA) is a group endogenous non-coding single strand RNA which is recognized to be involved in the development of epilepsy. Our preliminary data showed that miR-23a was up-regulated in the hippocampus of TLE animal models. Furthermore, we predicted and validated miR-23a target gene ADAM10. Based on our previous study, this project proposed a hypothesis that miR-23a-ADAM10 pathway regulates epileptogenesis and epilepsy-associated hippocampal pathological changes, which affect the excitability of hippocampal circuit. If this hypothesis is proved, we could suppress epileptogenesis and alleviate hippocampal injury by selectively interfering miR-23a-ADAM10 pathway and therefore prevent and cure epilepsy. In this project, we sought to determine the biological effect of miR-23a in TLE and to reveal the molecular mechanisms of how miR-23a regulation of epileptogenesis by using the methods of pharmacology and molecular biology in vitro and in vivo. We believe this study would give the perspective in seeking new therapeutic strategy and developing new anti-epileptic drugs.

微小RNA(microRNA，miRNA)是一类内源性非编码单链RNA分子，新近的研究发现miRNA在颞叶癫痫发生、发展过程中具有重要作用。申请者在预实验中发现miR-23a在颞叶癫痫模型小鼠海马组织中被显著上调，并通过生物信息学方法预测到miR-23a的靶基因ADAM10，且证实了miR-23a与ADAM10的靶向关系。本项目在前期研究的基础上，提出miR-23a→ADAM10通路调控癫痫发生并在癫痫发生后调控海马结构病理性损伤，影响海马神经环路兴奋性的新假说。如果该假说得到证实，将有望通过选择性干预miR-23a→ADAM10信号通路遏制癫痫发生，并在癫痫发生后减轻海马结构病理性损伤，达到有效控制癫痫疾病的目的。本项目拟通过药理学、分子生物学等手段，结合细胞与动物模型，在细胞和分子水平阐明miR-23a在颞叶癫痫疾病中的作用和调控机制，为探寻癫痫药物靶标提供前瞻性思路。

微小RNA (microRNA，miRNA) 是一类内源性非编码单链RNA分子，新近的研究发现miRNA在颞叶癫痫发生、发展过程中具有重要作用。在本课题研究中，我们发现miR-23a 在颞叶癫痫小鼠海马区的表达被显著上调，提示miR-23a在癫痫疾病中可能具有重要的作用。通过生物信息学方法进一步探索miR-23a下游作用靶点，我们发现去整合素和金属蛋白酶10基因 (A disintegrin and metalloprotease10，ADAM10) 为miR-23a作用的靶基因。我们的研究发现诱导癫痫发作后，miR-23a作为上游信号分子被激活，其通过阻遏下游靶基因ADAM10的表达，使神经元兴奋性增高引起癫痫发生，并在癫痫发生后引起海马结构病理性损伤如氧化应激和神经炎性反应而促进了异常兴奋性神经环路形成。该研究在细胞和分子水平阐明了miR-23a-ADAM10 通路调控颞叶癫痫疾病发生的机制，将为寻找癫痫疾病的潜在药物靶点以及探索癫痫疾病全新治疗理念和策略提供前瞻性思路。